This invention relates to a method for preparing a dosage form, such as a tablet, a bead or the like, with a controlled and delayed release of the active ingredient and the controlled release dosage form made by the process.
It is known to produce solid pharmaceutical or other functionally active preparations which ensure a sustained release of an active ingredient over a long period of time and thus ensure a constant concentration of active ingredient in the body. These delayed release forms make it possible to reduce the number of doses of the drug to be administered daily and thus simplify the treatment plan considerably. Usually delayed release tablets and capsules are provided with a coating which regulates the release of active ingredient.
One disadvantage of relying on coatings for the delayed release property is that any inadvertent puncture of the coating or division of the tablet critically affects the coating integrity or the total surface area of the tablet, that is, some of the barrier coating effectiveness is lost. As a result, the characteristics of the release of active ingredient are significantly altered, so that in many cases, the delayed release tablets no longer have the property of delayed and continuous release of an active ingredient.
In addition, tablets with score lines are known which enable the tablets to be divided into partial doses in order to meet special therapeutic requirements. Divisible tablets of this kind must, in particular, satisfy the requirement of being easy and safe to divide and of ensuring precise dosage, even when broken into fragments.
Microencapsulated formulations do not wholly overcome the problem of controlled release because the film-forming agent frequently forms a continuous phase after a period of time making it impossible to maintain reproducible release rates. U.S. Pat. No. 4,716,041 to Kjornaes et al. teaches a microencapsulated formulation of a first, inner film-forming coating, a second, outer film coating. The coated formulations are subsequently heated to permit the inner film-forming coating to form a continuous phase with uniform diffusion characteristics with time. Such a multiple coating process adds to the expense of a formulation and does not overcome the problem of coating integrity for tablets, caplets and other dosage forms.
Orally administerable pharmaceutical preparations are known in which the active substance is embedded in a polymer or matrix. The matrix slowly dissolves or erodes to release the pharmaceutically active ingredient. The feed formulations of pharmaceutical preparations of this kind are normally produced by dissolving the active ingredient together with a polymer in a solvent, then evaporating the solvent and granulating the solid mixture. Frequently the removal of the solvent and the granulation are carried out in a single operation by spray drying.
Pharmaceutical preparations of this type are intended for the purpose of distributing the active ingredient in a finely dispersed form through the polymer and increasing the surface area of the substance which is to be dissolved, so as to accelerate and not delay the dissolving process.
U.S. Pat. No. 4,547,359 teaches that a divisible polyacrylate-based tablet may be formed of a compressed composition comprising a finely divided polyacrylate material having the active ingredient incorporated therein in molecular dispersion, and conventional tablet excipients. However, the patent teaches it is particularly important to use a specific acrylate polymerized by emulsion polymerization and having a particle size of about 140 nm. Polyacrylates prepared by other methods, such as by solution or block polymerization, are unsuitable for purposes of the invention. In order to ensure a delayed release of the active ingredient, the active ingredient embedded in the polyacrylate material should have diffusion coefficients of 10.sup.-5 to 10.sup.-7 cm.sup.2 per hour. However, it is undesirable to restrict the pharmaceutically active compounds to such a narrow range of diffusion coefficients.
U.S. Pat. No. 4,692,337 to Ukigaya et al. teaches that prior art formulations based on a water-insoluble or slightly water soluble matrix have two disadvantages, the weight percentage of the matrix material must be 50% or more of the total weight, and that the rate of release of the medication rapidly decreases with time. Instead, the patent teaches dry mixing 100 parts of the active ingredient, theophylline, with 5 to 200 parts of ethyl cellulose and compressing the mixture into tablets.
Polylactic acid (PLA) is a well-known biologically compatible, insoluble polymeric body employed for the sustained release of pharmaceutical ingredients. U.S. Pat. No. 4,357,312 teaches an implantable matrix suitable for dispensing pharmaceutical ingredients in which the pharmaceutical ingredient is dissolved in a mixture of polylactic acid, solvent and water. Freezing the water creates channels, and subsequent drying removes the solvent and water. The freezing conditions must be carefully controlled to make the release of the pharmaceutical ingredient uniform.
U.S. Pat. No. 4,659,558 discloses bioerodable polymers useful to form coatings including polycarboxylic acids, polyamides, polylactic acid, polyglycolic acid and the like.
U.S. Pat. No. 4,666,702 teaches a drug delivery tablet containing a central core and a coating which is a thermoplastic polymer, optionally polylactic acid, nylon, polyglycolic acid and the like.
U.S. Pat. No. 4,652,441 teaches a microcapsule or bead suitable for controlled release of a water soluble pharmaceutical ingredient including an oil layer thickened with polylactic acid.